Neurotoxic alkaloids: saxitoxin and its analogs

Abstract

Saxitoxin (STX) and its 57 analogs are a broad group of natural neurotoxic alkaloids, commonly known as the paralytic shellfish toxins (PSTs). PSTs are the causative agents of paralytic shellfish poisoning (PSP) and are mostly associated with marine dinoflagellates (eukaryotes) and freshwater cyanobacteria (prokaryotes), which form extensive blooms around the world. PST producing dinoflagellates belong to the genera Alexandrium, Gymnodinium and Pyrodinium whilst production has been identified in several cyanobacterial genera including Anabaena, Cylindrospermopsis, Aphanizomenon Planktothrix and Lyngbya. STX and its analogs can be structurally classified into several classes such as non-sulfated, mono-sulfated, di-sulfated, decarbamoylated and the recently discovered hydrophobic analogs--each with varying levels of toxicity. Biotransformation of the PSTs into other PST analogs has been identified within marine invertebrates, humans and bacteria. An improved understanding of PST transformation into less toxic analogs and degradation, both chemically or enzymatically, will be important for the development of methods for the detoxification of contaminated water supplies and of shellfish destined for consumption. Some PSTs also have demonstrated pharmaceutical potential as a long-term anesthetic in the treatment of anal fissures and for chronic tension-type headache. The recent elucidation of the saxitoxin biosynthetic gene cluster in cyanobacteria and the identification of new PST analogs will present opportunities to further explore the pharmaceutical potential of these intriguing alkaloids.

Keywords: PSP; PSTs; STX; alkaloid analogs; neurotoxins; paralytic shellfish poisoning; paralytic shellfish toxins; saxitoxin.

Figure 1

The proposed transmembrane arrangement of the α-subunit of Na⁺ channels. The pore is represented in red, the voltage sensors in yellow and the inactivation gate in blue. PSP is mediated by the interaction and blockage of Site 1 by STX. Figure adapted from [30].

Figure 2

Biotransformation of the paralytic shellfish toxins. Refer to Table 1 for assigned R groups. Moieties highlighted in red indicate a differentiation from the structure of STX. Unbroken line refers to experimental data of toxin conversion. Broken line refers to putative biotransformation based on structural analysis.